Author ORCID Identifier
https://orcid.org/0000-0002-4424-5400
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Aron Lichtman
Second Advisor
Laura Sim-Selley
Third Advisor
Jolene Windle
Fourth Advisor
David Walentiny
Fifth Advisor
Joseph Porter
Abstract
Cannabinoid type-1 (CB1) allosteric modulators represent a promising approach to modulate CB1 receptor signaling by binding to distinct receptor sites, without producing adverse cannabimimetic and dependence-related effects associated with Δ9-tetrahydrocannabinol (THC) and other CB1 agonists. This dissertation investigates the pharmacological, behavioral, and dependence-related profiles of CB1 allosteric modulators for their therapeutic potential and misuse liability. Presented here, the chiral CB1 positive allosteric modulator (PAM) ZCZ011 was resolved into its R- and S-enantiomers and characterized across in vitro and in vivo assays. Both enantiomers enhance CB1 agonist activity and produce intrinsic effects in vitro. Behaviorally, they produce antinociceptive effects in the chronic constriction injury (CCI) neuropathic pain model, and attenuate withdrawal signs in THC-dependent mice, while lacking cannabimimetic effects. Notably, the absence of stereoselectivity suggests that pharmacological outcomes are driven by mechanisms mediating both PAM activity and intrinsic allosteric-agonism, rather than chirality. Complementary studies of ZCZ011 and the related CB1 PAM, GAT211, demonstrate that repeated administration produces rimonabant-precipitated withdrawal, but not spontaneous withdrawal, indicating reduced dependence liability relative to THC. In contrast, CBD failed to produce a discriminative stimulus, did not substitute for or negatively modulate CB1 agonist effects, and did not alter brain endocannabinoid levels despite achieving high systemic and central concentrations in vivo, supporting the conclusion that it lacks misuse liability. Collectively, these findings validate CB1 allosteric modulation as a viable strategy to retain efficacy of CB1 as a therapeutic target, while minimizing dependence-related outcomes. This work advances the field by emphasizing the importance of early in vitro characterization, evaluating the translational relevance of “pure” PAM and allosteric-agonists observations in vitro to the whole animal, and identifying the need for standardized experimental frameworks to improve reproducibility and cross-study interpretation.
Rights
© Mohammed Ali Mustafa
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-7-2026